Project Summary Research Aims: Cystic Fibrosis (CF) is a common lethal genetic disease that causes chronic bacterial infections and respiratory failure. Irreversible changes in airway structure and function occur in children with CF following infections with Staphylococcus aureus and Pseudomonas aeruginosa. Our long-term goal is to discover how these pathogens establish infection in the CF airway and to develop treatments to improve bacterial clearance. The CF pig model provides an unprecedented opportunity to visualize these early events in CF lung disease. The immediate focus of this project is to localize where S. aureus and P. aeruginosa attach in the uninfected CF pig airway. This information will help determine whether the site of bacterial attachment predicts whether bacteria are subsequently cleared or retained. Preliminary studies reveal that both S. aureus and P. aeruginosa bind to mucus derived from submucosal glands. In CF pigs, the detachment of mucus is impaired following methacholine treatment, and bacteria that bind to this mucus are retained. We will apply these methods to determine (1) which mucins are the preferred binding targets for S. aureus and P. aeruginosa, (2) whether environmental conditions associated with CF such as low bicarbonate or low pH favor binding or release of bacteria from mucus, and (3) whether mucolytic drugs such as dithiothreitol or DNase can promote clearance of mucus that binds bacteria. Candidate Career Goals: My long-term career goal is to develop as an independent physician-scientist focused on early infectious events in CF. The K08 award will provide protected time for research and advanced training necessary to complete my research plan. Dr. Michael Welsh will provide scientific and career mentorship. Together, we have designed a structured program of career development that builds upon my existing experiences in pulmonology and airway biology. This will include scholarly oversight by an established group of CF researchers, specific scientific meetings and coursework in bacterial pathogenesis, and focused training in scientific communication to optimize my opportunity for future research success. Environment: This research will be conducted in the Lung Biology and Cystic Fibrosis Center at the University of Iowa, which is internationally recognized for its contributions to the study of CF pathogenesis. The investigators and resources in this center have enabled many important discoveries relevant to CF pathogenesis, including recent discoveries about abnormalities of airway mucus that occur at birth in CF pigs. The Lung Biology and Cystic Fibrosis Center has an excellent record of training successful physician- scientists, making it an optimal environment for these studies.